The Diabetes Control and Complications Trial (DCCT, 1983-1993) compared intensive therapy aimed at near normal glycemia versus conventional therapy with no specific glucose targets in 1441 subjects with type 1 diabetes (T1DM). In 1993, after a mean follow-up of 6.5 yrs, the study showed conclusively that intensive therapy reduced the risks of retinopathy, nephropathy, and neuropathy by 35-76%, and that hyperglycemia was a primary determinant of complications. We also described potential adverse effects of intensive therapy; assessed its effects on cardiovascular disease (CVD) risk factors, neurocognition and quality of life; and projected the lifetime health-economic impact. DCCT intensive therapy was then adopted world-wide as standard-of-care for T1DM. The Epidemiology of Diabetes Interventions and its Complications (EDIC, 1994-present) is the observational follow-up study of the DCCT cohort, with 95% of those surviving actively participating. Most outcomes are evaluated annually. CVD events and deaths are carefully documented and adjudicated. EDIC has notably discovered that the early beneficial effects of intensive treatment on complications have persisted for over 10 years despite the similar HbA1c levels during EDIC in the two groups, termed metabolic memory. Notably, former intensive therapy also greatly reduced the risk of CVD events. DCCT/EDIC collaborators have also conducted numerous ancillary studies, with separate funding, most recently including measurement of cardiac function on cardiac MRI and measurement of biomarkers of oxidative stress and inflammation as determinants of complications. The overarching goals for the next 5 years are to follow at least 90% of the surviving cohort; to accurately describe the study-long effects of glycemia (HbA1c) and other established and putative risk factors on diabetes complications and the metabolic memory effects of prior DCCT intensive therapy; and to expand knowledge regarding T1DM and its complications by supporting collaborations for new research funding applications to maximally utilize the cohort, phenotypic data set, and collected biologic and genetic samples. The specific scientific aims are to 1) evaluate effects of risk factors, biomarkers and glycemia on risk of clinical CVD; 2) assess the long-term changes in CVD risk factors; 3) describe effects of DCCT intensive versus conventional therapy on mortality; 4) evaluate risk factors for severe retinopathy and nephropathy; 5) assess effects of diurnal glycemic variation on complications; and 6) conduct eight new research projects involving new measurements and analyses. PUBLIC HEALTH RELEVANCE: Patients with T1DM (1,500,000 in the US) are at risk of microvascular and cardiovascular complications that are a major cause of morbidity, mortality and health care cost. The DCCT/EDIC is continuing to describe the long term benefits of intensive therapy on increasingly more severe manifestations of these complications, and to explore the mechanisms by which hyperglycemia and non-glycemic factors lead to an increased risk of these adverse complications, potentially affording a future lifetime free of complications and normal life expectancy for future generations.